Olaf Burkhardt

Comparison of Pneumococcal Conjugate Polysaccharide and Free Polysaccharide Vaccines in Elderly Adults: Conjugate Vaccine Elicits Improved Antibacterial Immune Responses and Immunological Memory

BACKGROUND High functional antibody responses, establishment of immunologic memory, and unambiguous efficacy in infants suggest that an initial dose of conjugated pneumococcal polysaccharide (PnC) vaccine may be of value in a comprehensive adult immunization strategy. METHODS We compared the immunogenicity and safety of 7-valent PnC vaccine (7vPnC) with that of 23-valent pneumococcal polysaccharide vaccine (PPV) in adults >/=70 years of age who had not been previously vaccinated with a pneumococcal vaccine. One year later, 7vPnC recipients received a booster dose of either 7vPnC (the 7vPnC/7vPnC group) or PPV (the 7vPnC/PPV group), and PPV recipients received a booster dose of 7vPnC (the PPV/7vPnC group). Immune responses were compared for each of the 7 serotypes common to both vaccines. RESULTS Antipolysaccharide enzyme-linked immunosorbent assay antibody concentrations and opsonophagocytic assay titers to the initial dose of 7vPnC were significantly greater than those to the initial dose of PPV for 6 and 5 of 7 serotypes, respectively (P < .01 and P < .05, respectively). 7vPnC/7vPnC induced antibody responses that were similar to those after the first 7vPnC inoculation, and 7vPnC/PPV induced antibody responses that were similar to or greater than antibody responses after administration of PPV alone; PPV/7vPnC induced significantly lower antibacterial responses, compared with those induced by 7vPnC alone, for all serotypes (P < .05). CONCLUSION In adults, an initial dose of 7vPnC is likely to elicit higher and potentially more effective levels of antipneumococcal antibodies than is PPV. In contrast with PPV, for which the induction of hyporesponsiveness was observed when used as a priming dose, 7vPnC elicits an immunological state that permits subsequent administration of 7vPnC or PPV to maintain functional antipolysaccharide antibody levels.

Procalcitonin to Guide Initiation and Duration of Antibiotic Treatment in Acute Respiratory Infections: An Individual Patient Data Meta-Analysis

This individual patient data meta-analysis of clinical trials investigating procalcitonin algorithms for antibiotic decision making found no increased risk of death or setting-specific treatment failure but did find significantly lower antibiotic exposure across different acute respiratory infections and clinical settings.

Intravenous Tigecycline as Adjunctive or Alternative Therapy for Severe Refractory Clostridium difficile Infection

Clostridium difficile infection (CDI) has become more refractory to standard therapy. We describe 4 patients with severe refractory CDI who were successfully treated with tigecycline. Symptoms improved within 1 week. No relapses were observed. This favorable outcome suggests that tigecycline might be a useful alternative for treating severe refractory CDI.

Ertapenem Pharmacokinetics and Impact on Intestinal Microflora, in Comparison to Those of Ceftriaxone, after Multiple Dosing in Male and Female Volunteers

ABSTRACT The pharmacokinetics of ertapenem and ceftriaxone were investigated in an open, randomized, two-period crossover study after single- and multiple-dose administration in 10 healthy volunteers (five women and five men). Both antibiotics were administered intravenously once daily for 7 days at dosages of 1 g (ertapenem) and 2 g (ceftriaxone). The concentrations of the antibiotics in serum and urine were quantified by the agar well diffusion method bioassay and, in addition, for ertapenem only, by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). For ertapenem the maximum concentration of the drug in plasma (Cmax) was 256 mg/liter, the half-life was 20.7 h, and the area under the plasma concentration-time curve (AUC) was 830 mg · h/liter. The concentrations in fecal samples were (mean value) 37.2 and 32.7 mg/kg on day 4 and day 8, respectively. Ceftriaxone exhibited a mean Cmax of 315 mg/liter, a half-life of 7.6 h, and an AUC of 1,556 mg · h/liter. The mean concentrations in fecal samples were 153 and 258 mg/kg on day 4 and day 8, respectively. No accumulation of ertapenem or ceftriaxone was detected at steady state. A slightly but significantly decreased AUC for ertapenem was detected for the female volunteers. No serious adverse event was observed. Both antibiotics induced a marked decrease in the anaerobic microflora (4-log-unit decreases in lactobacilli, bifidobacteria, clostridia, and bacteroides) and Escherichia coli, whereas the number of enterococci increased (4 log units). A slight overgrowth of yeasts was observed with both regimens. In all cases the microflora returned to normal levels on days 21 to 35.

Effect of Protein Binding on the Pharmacological Activity of Highly Bound Antibiotics

ABSTRACT During antibiotic drug development, media are frequently spiked with either serum/plasma or protein supplements to evaluate the effect of protein binding. Usually, previously reported serum or plasma protein binding values are applied in the analysis. The aim of this study was to evaluate this approach by experimentally measuring free, unbound concentrations for antibiotics with reportedly high protein binding and their corresponding antimicrobial activities in media containing commonly used protein supplements. Free, unbound ceftriaxone and ertapenem concentrations were determined in bacterial growth medium with and without bovine/human serum albumin, as well as adult bovine serum and human plasma using in vitro microdialysis. The corresponding antimicrobial activity was determined in MIC and time-kill curve experiments using Escherichia coli ATCC 25922 and Streptococcus pneumoniae ATCC 6303 as test strains. A semimechanistic maximum effect model was simultaneously fitted to the data and respective EC50 (concentration at half-maximum effect) values compared. Protein binding differed significantly for ceftriaxone (P < 0.05) between human plasma (76.8 ± 11.0%) and commercially available bovine (20.2 ± 8.3%) or human serum albumin (56.9 ± 16.6%). Similar results were obtained for ertapenem (human plasma, 73.8 ± 11.6%; bovine serum albumin, 12.4 ± 4.8%; human serum albumin, 17.8 ± 11.5%). The MICs and EC50s of both strains were significantly increased (P < 0.05) for ceftriaxone when comparing human and bovine serum albumin, whereas the EC50s were not significantly different for ertapenem. Free, unbound antibiotic concentrations differed substantially between plasma and protein supplements and correlated well with antimicrobial efficacy. Therefore, free, active concentrations should be measured in the test system instead of correcting for literature protein binding values.

Soft tissue penetration of cefuroxime determined by clinical microdialysis in morbidly obese patients undergoing abdominal surgery.

Antibiotic prophylaxis is intended to prevent postoperative wound infections, a major source of morbidity and mortality in surgical patients. Cefuroxime is a well-established second-generation cephalosporin that is given preoperatively in surgery units at a standard dose of 1.5 g. It is therefore important to determine whether cefuroxime distributes to the interstitial space fluid (ISF) of subcutaneous (s.c.) soft tissues, especially in obese patients who are at a higher risk of surgical site infections. In a single centre, prospective, open-label study, six morbidly obese patients [body mass index (BMI)> or =40] undergoing abdominal surgery received a single intravenous dose of 1.5 g cefuroxime within 1h of incision. Blood and microdialysis samples from the ISF of skeletal muscle and s.c. adipose tissue were collected before, throughout and after surgery for up to 6h post-dosing. Cefuroxime concentrations were determined by high-performance liquid chromatography-ultraviolet (HPLC-UV). Total peak concentrations in plasma (C(max)) (66.8+/-18.9 microg/mL) were higher than free C(max) levels in the ISF of muscle (60.1+/-15.2 microg/mL) and s.c. adipose tissue (39.2+/-26.4 microg/mL). Mean area under the free concentration-time curve ratios of muscle/total plasma (1.0+/-0.2) or s.c. adipose tissue/total plasma (0.6+/-0.5) indicate that cefuroxime distributes into the ISF of these tissues. In conclusion, the findings of this pilot study indicate that cefuroxime distributes into the ISF of muscle and s.c. adipose tissue of morbidly obese patients undergoing abdominal surgery. Concentrations in the ISF of soft tissues following a single 1.5 g dose may be high enough to prevent infections with Gram-positive organisms but may be insufficient to prevent infections with Gram-negative organisms.

Dosing of daptomycin in intensive care unit patients with acute kidney injury undergoing extended dialysis—a pharmacokinetic study

BACKGROUND Daptomycin is a new intravenous cyclic lipopeptide antibiotic, licensed for the treatment of complicated skin and soft tissue infections caused by Gram-positive organisms including both susceptible and resistant strains of Staphylococcus aureus and for the treatment of various infections due to susceptible organisms, including serious and life-threatening Gram-positive infections, vancomycin-resistant enterococcal infections and right-sided endocarditis with associated bacteremia. Currently, no dosing recommendations exist for this drug for patients with acute kidney injury (AKI) undergoing renal replacement therapy. The aim of this study was to evaluate pharmacokinetics of daptomycin in critically ill patients with AKI undergoing extended dialysis (ED), a frequently used mean of renal replacement therapies in intensive care units (ICUs) around the world. Patients and methods. A prospective, single-dose pharmacokinetic study was performed in the medical and surgical ICUs of a tertiary care center. The aim was to investigate critically ill patients with anuric AKI being treated with ED and receiving daptomycin (n = 10). Daptomycin (6 mg/kg) was administered 8 h before ED was started. RESULTS Key pharmacokinetic parameters like half-life in critically ill patients treated with ED were comparable to healthy controls. The dialyser clearance for daptomycin was 63 +/- 9 ml/min. Based on the amount of the drug recovered from the collected spent dialysate, the mean fraction of the drug removed by one dialysis treatment was 23.3%. CONCLUSION Our data suggest that patients treated with ED using a high-flux dialyzer (polysulphone, 1.3 m(2); blood and dialysate flow, 160 ml/min; ED time, 480 min) and employing current dosing regimen, 6 mg/kg daptomycin every 48 h, run the risk of becoming significantly under dosed if one adheres to a twice daily dosing schedule that is recommended for patients on maintenance haemodialysis. Our data suggest that a daily dose of 6 mg/kg daptomycin is necessary in this special patient population to avoid under dosing, which may have detrimental effects in critically ill patients suffering from life-threatening infections.

Reduced spontaneous apoptosis in peripheral blood neutrophils during exacerbation of COPD.

A major feature of acute exacerbation of chronic obstructive pulmonary disease (COPD) is the accumulation of activated neutrophils in the bronchial tree. This phenomenon can be explained by an increased migration and/or by a prolonged survival due to an inhibition of spontaneous apoptosis. The aim of this study was to assess the apoptotic behaviour of peripheral blood neutrophils in COPD patients during an acute exacerbation. Thirty-six hospitalised COPD patients with an acute exacerbation and 10 healthy volunteers were included. Blood samples were obtained at admission, after 3–5 days and at discharge. Spontaneous apoptosis of isolated neutrophils was measured based on Annexin V‐PE binding and nuclear morphology after culturing for 18 h. At admission, significantly lower rates of spontaneous apoptosis were noted in COPD patients compared with healthy volunteers (mean±sd 31±13% versus 44±18%). The mean percentages of apoptotic neutrophils were 31±13% at admission, 39±15% after 3–5 days and 47±18% at discharge. There was a statistically significant difference between the rates of spontaneous apoptosis on the first day and at discharge. Neither forced expiratory volume in one second <35% predicted, smoking habit, corticosteroid therapy nor evidence of bacterial infection showed any influence on the spontaneous apopotosis in this study. In conclusion, during acute exacerbations of chronic obstructive pulmonary disease, neutrophil granulocytes show a reduced spontaneous apoptosis that increases progressively after treatment and clinical remission. This raises the question of the importance of neutrophil apoptosis in the development and resolution of exacerbations of chronic obstructive pulmonary disease.

Pharmacokinetics of ertapenem in critically ill patients with acute renal failure undergoing extended daily dialysis

BACKGROUND Extended (daily) dialysis (EDD) is an increasingly popular mode of renal replacement therapy in the ICU (intensive care unit) as it combines the advantages of intermittent haemodialysis (IHD) and continuous renal replacement therapy (CRRT), i.e. excellent detoxification accompanied by cardiovascular tolerability. The aim of this study was to evaluate pharmacokinetics (PK) of ertapenem, the newest carbapenem with once-daily dosing, in critically ill patients with anuric acute renal failure (ARF) undergoing EDD. PATIENTS AND METHODS In a single-centre, prospective, open-label study six ICU patients with ARF undergoing EDD were treated with 1 g ertapenem given as a single intravenous dose. EDD was performed using a high-flux dialyzer (polysulphone, 1.3 m(2)). Blood and dialysate flow were 160 mL/min, and the length of treatment was 480 min. Plasma samples were collected at different time-points up to 24 h after medication. Drug concentrations were determined by a validated LC-MS method. Free drug concentrations were estimated using a two-class binding site equation. RESULTS After a single dose of 1000 mg free ertapenem, protein-unbound plasma concentrations exceeded a MIC(90) value of 2 mg/L for >20 h after dosing. The clearance of the tested dialyzer was 38.5 +/- 14.2 mL/min. CONCLUSIONS In contrast to patients undergoing regular IHD, in which a dose reduction is required, our data suggest that in patients treated with EDD a standard dose of ertapenem (1 g/day), i.e. dose for patients without renal failure, is required to maintain adequate plasma drug levels.

Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis

BACKGROUND In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings. METHODS Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects. FINDINGS We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 [9%] deaths in 3336 procalcitonin-guided patients vs 336 [10%] in 3372 controls; adjusted odds ratio [OR] 0·83 [95% CI 0·70 to 0·99], p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (pinteractions>0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days [95% CI -2·71 to -2·15], p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 [95% CI 0·57 to 0·82], p<0·0001). INTERPRETATION Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance. FUNDING National Institute for Health Research.